Dermal αSMA ⁺ myofibroblasts orchestrate skin wound repair via β1 integrin and independent of type I collagen production

Abstract

Skin wound repair is essential for organismal survival and failure of which leads to non‐healing wounds, a leading health issue worldwide. However, mechanistic understanding of chronic wounds remains a major challenge due to lack of appropriate genetic mouse models. αSMA+ myofibroblasts, a unique class of dermal fibroblasts, are associated with cutaneous wound healing but their precise function remains unknown. We demonstrate that genetic depletion of αSMA+ myofibroblasts leads to pleiotropic wound healing defects, including lack of reepithelialization and granulation, dampened angiogenesis, and heightened hypoxia, hallmarks of chronic non‐healing wounds. Other wound‐associated FAP+ and FSP1+ fibroblasts do not exhibit such dominant functions. While type I collagen (COL1) expressing cells play a role in the repair process, COL1 produced by αSMA+ myofibroblasts is surprisingly dispensable for wound repair. In contrast, we show that β1 integrin from αSMA+ myofibroblasts, but not TGFβRII, is essential for wound healing, facilitating contractility, reepithelization, and vascularization. Collectively, our study provides evidence for the functions of myofibroblasts in β1 integrin‐mediated wound repair with potential implications for treating chronic non‐healing wounds.

Fibroblasts in Scar Formation: Biology and Clinical Translation

“…Under stimulation of PDGF and FGF from previously attracted inflammatory cells, granulation tissue is gradually formed by involvement of angiogenesis, as well as migration of fibroblasts [ 21 ]. With the accumulation, differentiation, and proliferation of fibroblasts, new ECM is produced, and wounds become slowly contracted [ 22 ]. The remodeling phase can last for a year or even longer, and apoptosis develops in most endothelial cells, macrophages, and fibroblasts, at this stage [ 23 ].…”

“…The significant upregulation of Connexin 43 (Cx43) in specialized fascia fibroblasts are known to be responsible for scar formation, while inhibition of Cx43 prevents collective migration of fascia En1-positive fibroblasts, which disrupts the repair of deep injuries [ 46 ]. Other wound-associated biomarkers include SMA α +, FAP+, and FSP1+ [ 22 ]. Meanwhile, high expression of FOXF2 is measured in scar fibroblasts, and knockdown of FOXF2 demonstrates declined scars and reduced collagen I.…”

Reoxygenation Modulates the Adverse Effects of Hypoxia on Wound Repair

“…Enhanced angiogenesis can accelerate the cell migration to the wound site, and thus promote collagen synthesis, granulation tissue formation and wound healing [39]. Since α-SMA is related to actin and integrin, α-SMA myofibroblasts are mediated by β1 integrin, and its high expression facilitates the migration and differentiation of fibroblasts to myofibroblasts, thus promoting granulation tissue formation, and promote re-epithelialization and angiogenesis [38,59]. Previous studies have shown that genetic depletion of αSMA myofibroblasts leads to multipotent wound healing defects, including a lack of re-epithelialization and granulation, impaired angiogenesis, and increased hypoxia, which are hallmarks of chronic non-healing wounds [59,60].…”

“…Since α-SMA is related to actin and integrin, α-SMA myofibroblasts are mediated by β1 integrin, and its high expression facilitates the migration and differentiation of fibroblasts to myofibroblasts, thus promoting granulation tissue formation, and promote re-epithelialization and angiogenesis [38,59]. Previous studies have shown that genetic depletion of αSMA myofibroblasts leads to multipotent wound healing defects, including a lack of re-epithelialization and granulation, impaired angiogenesis, and increased hypoxia, which are hallmarks of chronic non-healing wounds [59,60]. Our study demonstrates that reoxygenation treatment is essential for wound healing by promoting α-SMA expression, which in turn promotes wound contractility, re-epithelialization, and angiogenesis.…”

Toward Elucidating Epigenetic and Metabolic Regulation of Stem Cell Lineage Plasticity in Skin Aging

“…First and foremost, epithelial cells serve as the fundamental units of our barrier; they reside in the interfollicular epidermis and pilosebaceous unit, the latter including the sebaceous gland and the hair follicle ( Hardy, 1992 ; Fuchs, 1995 ; Paus and Cotsarelis, 1999 ; Watt, 2001 ; Lopez-Pajares et al, 2013 ). Fibroblasts in the dermis secrete bulk extracellular matrix in the tissue for not only structural support but also mediate signaling ( Gurtner et al, 2008 ; Sennett and Rendl, 2012 ; Heitman et al, 2019 ; Plikus et al, 2021 ; McAndrews et al, 2022 ). Subcutaneous adipocytes and dermal pre-adipocytes exhibit remarkable lineage plasticity to mediate metabolic and signaling regulations ( Horsley and Watt, 2017 ).…”